The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Rifaximin of Formula I, is an antibiotic belonging to rifamycin class of antibiotics and is chemically known as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S, 28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]-benzimidazole-1,15(2H)-dione, 25-acetate.

Rifaxitnin is an antibiotic pertaining to the rifamycin class, specifically it is a pyrido-imdazo rifamycin which is described in Italian patent IT 1154655. U.S. U.S. Pat. Nos. 4,341,785 and 4,557,866 disclose a process for the preparation of rifaximin starting from rifamycin S or O. The above patents describe purification steps of rifaximin by performing crystallization of crude rifaximin from a 7:3 mixture of ethyl alcohol/water and drying under atmospheric pressure and vacuum. These patents do not disclose the exact crystallization and drying conditions as well as any characterization data for confirmation on polymorphic forms of rifaximin.
U.S. Pat. No. 7,045,620 discloses three polymorphic forms α, β and γ of rifaximin. Form α and β show pure crystalline characteristics while the γ form is poorly crystalline. The US '620 discloses that the formation of the α, β and γ forms depends on the presence of water within the crystallization solvent, on the temperature at which the product is crystallized and on the amount of water present into the product at the end of the drying phase.
The polymorphic forms α, β and γ are characterized on the basis of water content and XRPD. This patent also discloses processes for preparation of these polymorphs which involve use of specific reaction conditions during crystallization like dissolving rifaximin in ethyl alcohol at 45 to 65° C., precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. The purely crystalline forms α and β are obtained by immediate filtration of suspension when temperature of reaction mixture is brought finally to 0° C. whereas in order to obtain the poorly crystalline form γ, the reaction mixture is stirred for 5-6 hours after temperature is set to 0° C. and then filtered the suspension. The α form has water content lower than 4.5%, for β form it should be higher than 4.5% and to obtain γ form, water content should be below 2%.
CystEngComm reference article Vol. 10, Pg. 1074-1081 (2008) discloses five crystal forms of rifaximin and their effect on pharmaceutical properties. Five distinct crystal forms of rifaximin (α, β, γ, δ and ε) have been identified and characterized by X-ray powder diffraction, solid state 13C NMR, and HATR-IR spectroscopy.
U.S. Pat. No. 7,709,634 discloses an amorphous form of rifaximin and the process for the preparation thereof.
U.S. Pat. No. 8,193,196 B2 discloses polymorphic forms δ and ε of rifaximin and methods of their preparation by dissolving rifaximin in ethyl alcohol at 45 to 65° C., precipitation by adding water to form a suspension, filtering the suspension and washing the resulted solid with demineralized water, followed by drying for a period of time between 2 and 72 hours until a water content in the range 2.5-6% is obtained.
U.S. Pat. No. 7,709,634 B2 discloses amorphous form of rifaximin characterized by x-ray powder diffraction pattern as shown in FIG. 1.
U.S. Pat. No. 8,633,234 B2 discloses amorphous form of rifaximin characterized by x-ray powder diffraction pattern as shown in FIG. 1.
U.S. Pat. No. 8,067,429 B2 discloses several polymorphic forms of rifaximin such as ζ, form η, form-i, form ι-dry, form i-dry′, form B, amorphous form and form Θ. Main differentiating point of these polymorphs is respective water content and x-ray powder diffraction pattern.
International PCT Publication No. WO 2013/027227 A1 discloses crystalline Form-I of rifaximin and process for its preparation.
International PCT Publication No. WO 2015/159275 A2 discloses crystalline Form G of rifaximin and process for its preparation.
It is evident from above, that rifaximin can exist in number of polymorphic forms, formation of these polymorphic forms depends upon specific reaction conditions applied during crystallization and drying. In recent times, the solid-state properties of drugs have received great attention as a major contributing factor to both bio-availability and formulation characteristics in the pharmaceutical industry. While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement thereof and exhibit different physical properties such as melting point, shape, particle size, X-ray diffraction pattern, infrared absorption, and solid state NMR spectrum, density, hardness, stability, and dissolution. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
Other examples are known, where different crystalline forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amorphous form of the substance. The solid-state experts are in a constant search for crystalline forms that are chemically and physically more stable and can withstand physical stress and still retain their original properties.
Rifaximin exists in a variety of crystalline or amorphous form or a mixture of amorphous and crystalline form having distinct crystal structures and physical properties. Consequently, there is an ongoing search for a new polymorphic form of drug, which may provide improved performance thereof.